1. Field of the Invention
The invention relates to novel chemical compositions and methods for the resection of the exocrine portion of the pancreas.
2. Discussion of the Prior Art
Pancreatic tumors result in the death of more than 95% of afflicted patients [Isselbacher et al, (ed.) Harrison's Principles of Internal Medicine, 13th edition, pages 1532-1534 (1994)]. More than 26,000 people die each year in our country from pancreatic adenocarcinoma. It is the fourth most common cause of cancer death in men and the fifth most common for women. Overall, it is the fourth most common carcinoma after those of the lung, colon and breast. The incidence of this disease is linear with age to sixty, but its occurrence increases markedly in the seventh or eighth decade of life. There are several different histologies associated with cancer of the pancreas, including small cell cancer, cystadenocarcinoma, islet cell tumors, lymphoma and carcinoid; however, 75-80% of the cases involve adenocarcinomas of ductal origin.
Pancreatic tumors occur twice as frequently in the pancreatic head (60% of cases) as in the body (15-20%) or tail (about 5%) of the gland [Cotran et al, (ed.) Rubbins Pathologic Basis of Disease, 4th edition, pages 988-992 (1989)]. Currently, complete surgical resection of pancreatic tumors offers the only effective treatment of this disease. Surgical resection, however, is limited, for all practical purposes, to those individuals having tumors in the pancreatic head and in whom jaundice was the initial symptom. Even with the operation, the five-year survival rate for these patients is only 5% [Isselbacher et al, supra]. Only 15-25% of tumors are resectable at the time of diagnosis and only 10-20% of patients resected will survive more than two years. With these less than satisfactory surgical results, present day therapy has evolved in two directions: palliation of symptoms and aggressive multimodality treatment regimes which combine surgery with chemotherapy and radiation treatment.
Located in the upper abdomen in the retroperitoneum, the pancreas is associated intimately with many major structures, including the portal vein, stomach, duodenum, common bile duct and the superior mesenteric artery. As the tumor grows, the patient's symptoms result from tumor infiltration of surrounding structure causing pain, nausea, vomiting, weight loss and jaundice. The latter condition presents symptoms in no more than one-half of the patients. Once tumor infiltration occurs, other structures such as the portal vein become affected and this precludes curative resecting of the pancreas.
Effective treatment of pancreatic cancer must achieve two difficult goals: control of the primary tumor mass, both initially and subsequently, and treatment of the metastatic tumor cells. As a result of its insidious onset, the diagnosis of pancreatic cancer is delayed frequently for several months. This delay has profound implications since metastatic spread to the liver or lymph nodes has been observed at a time of diagnosis in 60% of patients and this factor diminishes the prospect for long-term survival. Also, there are no known specific markers of carcinoma of the pancreas and it is asymptomatic in its early stage.
Palliative therapy has become a major thrust of current treatment. Initial relief of symptoms has relied on surgery with surgical by-pass of gastric outlet obstruction and operative by-pass of biliary obstruction. Subsequent symptomatic treatment has centered around endoscopic placement of biliary stents to by-pass tumors blocking the biliary tract and/or percutaneous placement of by-pass conduits.
Aggressive multimodality therapy combining chemotherapy and radiation therapy has been the response of choice when surgery alone was not effective. Radiation has been the cornerstone of therapy for non-resectable cancer of the pancreas and 5-fluorouracil (5-FU) chemotherapy has been an important adduct to radiation treatment in these patients. However, despite these valiant efforts, few patients survive five years.
Effective radiotherapy needs to maximize exposure of the affected tissues while sparing normal surrounding tissues. Interstitial therapy, where needles containing a radioactive source are embedded in the tumor, has become a valuable new approach. In this way, large doses of irradiation can be delivered locally while sparing the surrounding normal structures. Intraoperative radiotherapy, where the beam is placed directly onto the tumor during surgery while normal structures are moved safely away from the beam, is another specialized radiation technique. Again, this achieves effective irradiation of the tumor while limiting exposure to surrounding structures. However, despite the obvious advantage of approaches predicated upon local control of the irradiation, patient survival is not significantly improved.
The foundation of chemotherapy for carcinoma of the pancreas has employed 5-FU. Here, too, the prognosis is bleak: no better than 10-15% of patients treated with 5-FU will experience a significant reduction in tumor size; overall survival rates are not improved. The addition of other chemotherapeutic agents such as cis-platin or adriamycin has not dramatically improved disease management. For this reason, attempts to augment the intrinsic activity of 5-FU have been undertaken. In one approach, 5-FU is converted to 4-fluorode-oxyuridine monophosphate (FdUMP) which binds covalently to thymidylate synthase. This competitive inhibitor disrupts DNA replication by curtailing deoxyuridine monophosphate anabolism to deoxythymidine.
New experimental efforts in treating pancreatic cancer have been initiated; however, their limited success emphasizes the need for radically new approaches in the management of this devastating disease.
There exist, of course, other pancreatic pathologies which require intervention for their relief, e.g., pancreatitis.
It is an object of the present invention to provide novel compositions and methods for the chemical resection of all or a portion of the pancreas in human or non-human mammals.